Impact of Intensive Treatment of SBP on Brain Perfusion, Amyloid, and Tau (IPAT Study)

Inclusion Criteria:

• Age 60-85, all races/ethnicities, and both sexes are eligible;

• Mini-Mental State Exam (MMSE) ≥ 26 to exclude gross dementia; based on clinicaljudgment, may be rescreened in ≥ 7 days;

• Individuals with SBP ≥ 130 and SBP ≤ 180 if on 0 or 1 antihypertensive medications; ≥130 and ≤170 on up to 2 medications; ≥130 and ≤160 on up to 3 medications; ≥130 and ≤150 on up to 4 medications. Those on antihypertensives are eligible. If anindividual, not treated for hypertension (HTN), has a SBP ≥ 125 mmHg, considerrescreening after 24 hours;

• Willingness to be randomized into the treatment groups and ability to return toclinic for follow-up visits over 24 months;

• Fluency in English or Spanish or both, adequate visual and auditory acuity to allowneuropsychological testing;

• Participants must have a regular healthcare provider.

Exclusion Criteria:

• Clinically documented history of stroke, focal neurological signs or other majorcerebrovascular diseases based on clinical judgment or MRI/CT scans such as evidenceof infection, infarction, or other brain lesions;

• Diagnosis of AD or other type of dementia, or significant neurologic diseases suchas Parkinson's disease, seizure disorder, multiple sclerosis, history of severe headtrauma or normal pressure hydrocephalus;

• Evidence of severe major depression (GDS ≥ 12, may be rescreened after 12 weeks orlonger if evidence of reactive depression or temporary mood disturbances) orclinically significant psychopathology, (e.g., psychosis and schizophrenia); ifhospitalized in past year, can be rescreened in 6 months; or presence of a majorpsychiatric disorder that in the investigator's opinion, could interfere withadherence to research assessments or procedures.

• Unstable heart disease based on clinical judgment (e.g., heart attack/cardiacarrest, cardiac bypass procedures within previous 6 months and congestive heartfailure), or other severe medical conditions;

• History of atrial fibrillation and evidence on ECG with any of the following: activesymptoms of persistent palpitation, dizziness, history of syncope, chest pain,dyspnea, orthopnea, shortness of breath at rest, or paroxysmal nocturnal dyspneawithin the past 6 months; resting heart rate of < 30 or > 110 bpm; taking class I orIII antiarrhythmic drugs including flecainide, propafenone, dronedarone, sotalol,dofetilide, and amiodarone; or clinical concerns for safely participating inlowering blood pressure.

• Systolic BP equal or greater than 180 mmHg and/or diastolic BP equal or greater than 110 mmHg, may be rescreened in 1 week.

• Orthostatic hypotension, defined as the third standing SBP < 100mmHg, may berescreened after 2 weeks;

• History of significant autoimmune disorders such as systemic lupus erythematosus,rheumatoid arthritis or polymyalgia rheumatica;

• Significant history of alcoholism or drug abuse within the last five years;

• Uncontrolled diabetes mellitus, defined as hemoglobin A1C > 7.5%, or requiringinsulin treatment;

• Regularly smoking cigarettes within the past year;

• Pacemaker or other medical device of metal that precludes performing MRI;

• Women with a potential for pregnancy, lactation/childbearing (2 year post-menopausalor surgically sterile to be considered not childbearing potential);

• Participant enrolled in another investigational drug or device study, eithercurrently or within the past 2 months;

• Severe obesity with BMI > 40 ; clinical judgment should be applied in all cases toassess patient safety and anticipated compliance;

• Allergy to angiotensin receptor blockers (ARBs), i.e., drugs that have a suffix "-sartan"; allergy to amlodipine;

• Abnormal screening laboratory tests (e.g., liver ALT and AST > 3 x ULN, GFR < 30 orHct < 28%); may be rescreened after 2 weeks or longer;

• A medical condition likely to limit survival to less than 3 years;

• Participant has any condition(s) judged by the study investigator to be medicallyinappropriate, risky or likely to cause poor study compliance. For example:

1. Plans to move outside the clinic catchment area in the next 2 years;

2. Significant concerns about participation in the study from spouse, significantother, or family members;

3. Lack of support from primary health care provider;

4. Residence too far from the study clinic site such that transportation is abarrier including persons who require transportation assistance provided by thestudy clinic funds for screening or randomization visits;

5. Residence in a nursing home; persons residing in an assisted living orretirement community are eligible if they meet the other criteria;

6. Other medical, psychiatric, or behavioral factors that, in the judgment of thesite PI or clinician, may interfere with study participation or the ability tofollow the study Protocol.

7. Couples or significant partners who live together cannot be enrolled orparticipate simultaneously in the study.